The present invention relates to a commercial process for the production of (S)-1,2,3,4-tetrahydro-6,7-dialkoxy-3-isoquinolinecarboxylic acid compounds (1) and their derivatives from Levodopa (L-Dopa). The ultimately prepared compounds are used as intermediates for, but not limited to, the preparation of substituted derivatives of 1,2,3,4-tetrahydro-6,7-dialkoxy-3-isoquinolinecarboxylic acid such as those described in U.S. Pat. No. 4,344,949. 
The ACE inhibitor moexipril hydrochloride contains the 1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylic acid moiety in its structure, and it is known that the enantiomer possessing the (S) or (L)-configuration is required for optimum ACE inhibitory activity. This is disclosed in U.S. Pat. No. 4,344,949, and in Klutchko, S. et al. J. Med. Chem. 1986, 29, pp. 1953-1961 xe2x80x9cSynthesis of Novel Angiotensin Converting Enzyme Inhibitor Quinapril and Related Compounds. A Divergence of Structure-Activity Relationships for non-Sulfhydryl and Sulfhydry Typesxe2x80x9d. The prior art synthetic techniques for enantiomerically-enriched 1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylic acid requires an enantiomerically-enriched L-3,4-dimethoxyphenylalanine precursor, which was made by asymmetric hydrogenation of xcex1-amino-3,4-dimethoxycinnamic acid derivatives (O""Reilly, N. J. et al. U.S. Pat. No. 4,912,221) or enzymatic transamination of 3,4-RO(R1O)C6H3CH2COxe2x80x94CO2H (DE 2148953) or enzymatic/chemical resolution (U.S. Pat. No. 3,669,837, GB 1241405). These approaches have limited commercial use due to cost and the necessity for specialized equipment. Also, the prior art synthetic technique have failed to produce compounds having optical purity levels of over 97% ee. The designation %ee (enantiomeric excess) represents: [(amount of desired isomerxe2x88x92amount of undesired isomer)/total amount of both isomers]xc3x97100%. Therefore, an efficient method for preparing enantiomerically-enriched (S)-1,2,3,4-tetrahydro-6,7-dialkoxy-3-isoquinolinecarboxylic acid compounds (1) and their derivatives was needed to overcome the above deficiencies.
According to an aspect of the present invention there is provided a method for the preparation of (S)-1,2,3,4-tetrahydro-6,7-dialkoxy-3-isoquinolinecarboxylic acid compounds and their derivatives represented by the general formula 1: 
which process comprises reacting Levodopa of formula 2 with formaldehyde or formaldehyde precursors to obtain (S)-1,2,3,4-tetrahydro-6,7-dihydroxy-3-isoquinolinecarboxylic acid of formula 3; protecting the amino group of the compound of formula 3; alkylating the phenol groups of formula 4 to form compound of formula 5; and esterifying the carboxylic acid of formula 5 and optionally removing the N-protecting group. 
where R1 is hydrogen, lower alkyl, C2-C12 acyl, or R1O together are methylenedioxy. When R1 is a lower alkyl group, the preferred substituents are those of 1 to 9 carbon atoms. R2 is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, aralkyl or substituted aralkyl group. When R2 represents an alkyl group, the preferred alkyls are those of 1 to 8 carbon atoms. R3 is hydrogen, C2-C12 acyl group, benzyl, alkoxycarbonyl group, or aralkoxycarbonyl group. The process of instant invention provides an enantiomerically-enriched compound useful for, but not limited to, preparing moexipril and salts thereof. The preferred enantiomerically-enriched compounds obtained by the instant invention are (S)-1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylic acid, (S)-1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylic acid benzyl ester, and (S)-1,2,3,4-tetrahydro-6,7-diethoxy-3-isoquinolinecarboxylic acid. According to a further aspect of the invention, there are provided processes for making moexipril and salts thereof by reacting known compound of formula 9 
with compound of formula 1 wherein compound of formula 1 is (S)-1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylic acid or (S)-1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylic acid benzyl ester. The coupling of compound (1) prepared according to instant invention with compound of formula 9 may be carried out by traditional method known to those skilled in the art.
The present invention also relates to new intermediate compounds of formulas A and B, useful for, but not limited to, the production of substituted acyl derivatives of tetrahydroisoquinoline carboxylic acids. 
In accordance with the present invention, the (S)-1,2,3,4-tetrahydro-6,7-dialkoxy-3-isoquinolinecarboxylic acid compound (1) and their derivatives are prepared from commercially available and inexpensive material Levodopa (2) (L-Dopa) in high yield.
Surprisingly, the absolute (S)-configuration of Levodopa was transferred to compound (1) after multistep transformation. The starting material Levodopa (2) is a drug used for the treatment of Parkinson""s disease, and can be obtained in one step enzymatically from L-tyrosine, which is an inexpensive, readily available amino acid. Scheme 1 outlines the method utilized for the preparation of the compound (1). 
wherein R1, R2, R3 are defined as above. P could be hydrogen or various amino protective groups. For a comprehensive review of amino protective groups, see Greene, T. W. and Wuts, P. G. M., xe2x80x98Chapter 7. Protection for the Amino Groupxe2x80x99, in xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, Second Edition, John Wiley and Sons, Inc., 1999, pp. 494-653. In this context, the preferred groups are selected from C2-C12 carbonyl group, benzyl, aralkoxy and alkoxycarbonyl groups.
The preparation of (S)-1,2,3,4-tetrahydro-6,7-dihydroxy-3isoquinolinecarboxylic acid (3) comprises reacting its precursor Levodopa (2) with formaldehyde or formaldehyde precursor, for example paraformaldehyde, in the presence of an acid or mixture of acids. [Some Isoquinoline Derivativesxe2x80x9d (J. Org. Chem. 1961, 26, pp. 3533-3534) and Brossi, A. et al. xe2x80x9cxe2x80x98Alkaloidsxe2x80x99 in Mammalian Tissues. I. Condensation of L-Dopa and its two Mono-O-methyl Ethers with Formaldehyde and Acetaldehydexe2x80x9d (Helv. Chim. Acta, 1972, 55, pp.15-21)].
The amino group in compound (3) is protected by amino protective groups, such as carbamates, amides, alkyl, aryl, silyl and sulfenyl derivatives, to form compound (4). The compounds (3) or (4) are then reacted with O-alkylating reagents to produce the compound (1).
The novel process of this invention provides the following advantages:
The overall chemical yield and the procedure is suitable for large scale production and does not require specialized equipment. Starting material Levodopa (2) is commercial available and inexpensive. Levodopa can also be obtained in one step enzymatically from L-tyrosine. The absolute (S)-configuration of Levodopa (2) could be transferred to compound (1) after multistep transformation. If Levodopa is made from L-tyrosine, the chirality of compound (1) ultimately comes from L-tyrosine.
In the present invention, (S)-1,2,3,4-tetrahydro-6,7-dialkoxy-3-isoquinolinecarboxylic acid compounds and their derivatives are prepared from Levodopa with high chemical and optical purity and in good to excellent yield.
Scheme 2 depicts such a process, where R1 is hydrogen, lower alkyl, C2-C12 acyl, or R1O together are methylenedioxy. When R1 is a lower alkyl group, the preferred substituents are those of 1 to 9 carbon atoms. R2 is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, aralkyl or substituted aralkyl group. When R2 represents an alkyl group, the preferred alkyls are those of 1 to 8 carbon atoms. R3 is hydrogen, C2-C12 acyl group, benzyl, alkoxycarbonyl group, aralkoxycarbonyl group. P is hydrogen, C2-C12 acyl groups, benzyl, alkoxycarbonyl or aralkoxycarbonyl groups. 
Levodopa (2) is reacted with formaldehyde or formaldehyde precursors, for example paraformaldehyde, in a solution in the presence of an acid or a mixture of the acids, such as hydrochloric acid, sulfuric acid, nitric acid, and the like, to produce (S)-1,2,3,4-tetrahydro-6,7-dihydroxy-3-isoquinolinecarboxylic acid (3).
The protective groups for the protection of the amino moiety in compound (3) is selected from carbamates, amides, alkyl, aryl, silyl, sulfenyl and sulfonyl derivatives. The preferred carbamates are selected from methyl carbamate, ethyl carbamate, t-butyl carbamate, benzyl carbamate, t-amyl carbamate, cyclohexyl carbamate, isobutyl carbamate, and the like. The compound (3) is reacted with alkyl or aryl chloroformate or dialkyl or diaryl dicarbonate in the presence of a base or a mixture of bases in a suitable solvent or solvent mixture. The preferred amides can be selected from N-formyl, N-acetyl, N-benzoyl, N-picolinoyl, N-3-phenylpropionyl, N-4-pentenoyl, N-3-pyridylcarboxamido, and the like. The preferred alkyl, aryl or aralkyl groups are benzyl and its derivative. The preferred N-silyl groups are trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, and the like. The preferred N-sulfenyl and N-sulfonyl groups are benzenesulfenamide, triphenylmethylsulfenamide, p-toluenesulfonamide, benzenesulfonamide, and the like.
Both compounds (3) and (4) can be subjected to O-alkylation by treatment with an alkylating reagent in the presence of a base or a mixture of bases in a suitable solvent or solvent mixture. The alkylation reagents can be selected from alkyl or aryl halides, alkyl and aryl p-toluenesulfonate, alkyl and aryl methanesulfonate, alkyl and aryl trifluromethanesulfonate, dialkyl sulfates, and the like. The preferred reagents include benzyl bromide, benzyl chloride, methyl iodide, methyl bromide, ethyl iodide, ethyl bromide, methyl methanesulfonate, methyl p-toluenesulfonate, dimethyl sulfate, diethyl sulfate, and the like. When R1O together are methylenedioxy, the alkylation reagents can be selected from dichloromethane, dibromomethane, and the like. The base can be an inorganic or an organic base. The preferred bases are sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, triethylamine, tributylamine, pyridine, and the like.
The carboxylic acid group in compounds (3), (4) and (1) also can be alkylated by reacting the compound with an alcohol or an alkylene in the presence of an acid or a mixture of acids. The preferred alcohols are methanol, ethanol, benzyl alcohol, or the like. The preferred alkylenes are isobutylene, and the like. The acid can be inorganic and organic, such as hydrochloric acid, sulfuric acid, nitric acid, acetic acid, methanesulfuric acid, hydrogen chloride, trimethylsilyl chloride, polylphosphoric acid, p-toluenesulfonic acid, and the like. If necessary, the N-protective group can be removed by standard chemical methods, which have been well described in the prior art.
A more specific method is described in Scheme 3, wherein P is the protective group for the amino group, and is defined as below. R1 is hydrogen, lower alkyl, C2-C12 acyl, or R1O together are methylenedioxy. When R1 is a lower alkyl group, the preferred substituents are those of 1 to 9 carbon atoms. R2 is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, aralkyl or substituted aralkyl group. When R2 is an alkyl group, the preferred alkyls are those of 1 to 8 carbon atoms. 
Levodopa (2) is reacted with formaldehyde or formaldehyde precursors, for example paraformaldehyde, in a solution in the presence of an acid or a mixture of the acids, such as hydrochloric acid, sulfuric acid, nitric acid, p-toluenesulforic acid and the like. The concentration of the acid can range from 0.1 N to 10 N. The preferred concentration is from 0.2 N to 2 N. The amount of the acid or acids mixture can range from 0.5 to 10 moles per mole of Levodopa, and the preferred amount is from 1.0 to 3.0 moles per mole of Levodopa. The solvent used in this reaction can be selected from water, alcohols, or mixtures. The temperature of this reaction can range from xe2x88x9250xc2x0 C. to 100xc2x0 C. The preferred temperature is 0xc2x0 C. to 50xc2x0 C. After complete reaction, the mixture is treated with a base or a mixture of bases, and compound (3) precipitates from the reaction mixture. The product can be collected by filtration. Suitable bases include organic or inorganic base, such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, triethylamine, tributylamine, pyridine, and the like. The chemical yield of the reaction ranges from 50% to 100%, and the typical yields range from 80%-99%.
The protective groups (P) for the protection of amino group in compound (3) are selected from carbamates, amides, alkyl, aryl, silyl, sulfenyl and sulfonyl derivatives. After complete reaction, the mixture is treated with an acid or a mixture of acids, and compound (4) is isolated by filtration or solvent extraction.
The resulting compound (4) is treated with an alkylating reagent in the presence of a base or a mixture of bases in a suitable solvent or solvent mixture to alkylate the phenol groups or carboxylic group, or both. The preferred reagents include benzyl bromide, benzyl chloride, methyl iodide, methyl bromide, ethyl iodide, ethyl bromide, methyl methanesulfonate, methyl p-toluenesulfonate, dimethyl sulfate, diethyl sulfate, and the like. When R1O together are methylenedioxy, the alkylation reagents can be selected from dichloromethane, dibromomethane, and the like. The base can be inorganic or organic. Preferred bases are sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, triethylamine, tributylamine, pyridine, and the like. The solvent used in this reaction can be water, alcohols, ketones, benzene, toluene, ethers, dichloromethane, chloroform, and the like, and their mixtures. The temperature of this reaction can range from xe2x88x9250xc2x0 C. to 150xc2x0 C. The preferred temperature range is 0xc2x0 C. to 100xc2x0 C.
The amino protective group in compound (5a) or (5b) can be removed by standard deprotection techniques, for example, treatment of (5a) or (5b) with an acid or a base, or hydrogenolysis, to produce (S)-1,2,3,4-tetrahydro-6,7-dialkoxy-3-isoquinolinecarboxylic acid compound (6a) or its ester (6b). 
The compound (5a) can also be esterified with an R2X or an alkylene in the presence of base or acid as described in Scheme 4 to produce (S)-1,2,3,4-tetrahydro-6,7-dialkoxy-3-isoquinolinecarboxylic acid R2 ester 6, wherein R2 is selected from C1-10 alkyl or aryl groups, such as methyl, ethyl, propyl, isopropyl, butyl, benzyl, isobutyl, tert-butyl, and the like. X is selected from chloro, bromo, iodo, hydroxy, p-toluenesulfonate, methanesulfonate, trifluromethanesulfonate, and the like. The preferred alkylenes are isobutylene, and the like. The acid can be an inorganic or organic acid, such as hydrochloric acid, sulfuric acid, nitric acid, acetic acid, methanesulfuric acid, HCl gas, trimethylsilyl chloride, polylphosphoric acid, p- toluenesulfonic acid, and the like. The preferred bases are sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, lithium hydroxide, lithium carbonate, triethylamine, tributylamine, isopropyldiethylamine, and the like. The amino protective group could be removed during esterification, or by a separate reaction.